Translational failure of anti-inflammatory compounds for myocardial infarction: a meta-analysis of large animal models

Background

As a consequence of adverse remodelling, acute myocardial infarction (MI) may progress to chronic heart failure. Remodelling involves infarct expansion, myocardial scar thinning and left ventricular geometrical adaptation [1] and appears to stem from an exaggerated inflammatory response initiated during ischaemia and early reperfusion [2,3].
Inflammatory cells are attracted to damaged tissue. Factors released by the cells clear necrotic cells, which paves the way for scar formation [4]. The inflammatory process is important for stabilisation of scar tissue [5], but its acute effects cause infarct expansion and cardiac function worsening early after ischaemia in the reperfusion phase [6-8].
Based on observations in clinical studies, attenuating the inflammatory response has been hypothesised to be a promising strategy to limit infarct size and preserve cardiac function post-MI. Anti-inflammatory strategies have been shown to have efficacy in reducing reperfusion damage and post-MI remodelling in larger animal models [9], since these more closely resemble human anatomy, haemodynamics and pharmacodynamics.
None of these findings has been reproduced in clinical trials [10,11]. The more complex situation of humans, including presence of comorbidities and behaviour like smoking, as compared with large animal models, may yield a different post-MI inflammatory response. But a possible publication bias and experimental set-up of animal studies may also be relevant.
This study aimed to better understand the translational failure of anti-inflammatory compounds for MI. A meta-analysis was conducted to assess the overall effect of anti-inflammatory compounds in large MI studies, and methodological factors that influenced the outcome were identified by meta-regression. 183 publications were included that reported data on the primary outcome infarct size as percentage of area at risk (IS/AAR) from 3331 animals.

Main results

Anti-inflammatory treatment gave a mean reduction of IS/AAR of 12.7% (95%CI: 11.1-14.4%, P<0.001). Substantial heterogeneity between studies was seen and there was evidence for a publication bias of small studies.

After anti-inflammatory treatment, a smaller mean infarct size as percentage of the left ventricle (IS/LV) was seen (difference: 3.9%, 95%CI: 3.1-4.7%, P<0.001), as well as a higher ejection fraction (3.4, 95%CI: 0.8-6.1, P<0.001), as compared with controls. No difference in mortality was observed (OR: 0.96, 95%CI: 0.79-1.17, P=1.0).

Conclusion

These data from over 180 studies in large animals confirm that treatment with anti-inflammatory compounds reduce infarct size in these animals. The effect on infarct size appears to depend on the inflammatory pathway that is targeted, since leukotriene inhibitors were more effective than NSAIDs or immunosuppressive drugs. A difference in cardiac tissue after MI between patients and large animal models could lie in the role of inflammatory cells, which might be more important in patients. It might be better to ‘fine-tune’ rather than completely abolish the inflammatory response in patients and also optimal timing of therapy may be different between species.
The study also identified methodological aspects that were predictors of effect size. These should be taken into account to chose clinically relevant animal models to increase the translational value of preclinical research.

Editorial comment [12]

The authors call the above paper a “welcome reminder that, before moving into the clinical arena, we should carefully assess whether the experimental data available are sufficiently convincing and solid to allow a reasonable possibility of success in patients.” They also highlight that an important difference between patients and animal models may be that patients show large variability with regard to many aspects, while in animal models researchers try to obtain a reproducible site of coronary occlusion and duration of ischaemia. Also, experiments are typically performed in healthy young animals, while most patients with acute coronary syndromes are older and they may have a range of comorbidities and possibly under chronic drug treatment. “The ESC Working Group ‘Cellular Biology of the Heart’, aimed at improving pre-clinical assessmentof cardioprotective therapies called for multicentric randomized animal studies, as it is done in the context of clinical trials, to obtain more robust data.” In addition, the authors propose “it would seem wise to move away from the ‘cleanest’ possible experimental model, and start investigating new therapies under conditions that are more akin to the common clinical scenario.”